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Comment on 'A PAX6 gene polymorphism is associated with genetic predisposition to extreme myopia'

Zayats, Tetyana, Guggenheim, Jeremy Andrew ORCID:, Hammond, C. J. and Young, Terri L. 2008. Comment on 'A PAX6 gene polymorphism is associated with genetic predisposition to extreme myopia'. Eye 22 (4) , pp. 598-599. 10.1038/sj.eye.6703096

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Sir, Tsai et al1 carried out a case–control association study in 340 Taiwanese medical students, and reported an association between presence of ‘extreme myopia’ (<?10.00?D) and genotype at SNP rs667773 (also known as IVS9-12C to T) in the PAX6 gene. No association was found between ‘high myopia’ (<?6.00?D) and rs667773 genotype. rs667773 has a minor allele frequency (MAF) 4% in the United Kingdom; 7% in CEPH Europeans; 11% in Japan, and has been suggested to be a neutral polymorphism unlikely to cause an overt phenotype such as aniridia.2, 3 No common (neutral) PAX6 variants have been associated with myopia susceptibility.4, 5 We suggest that until replicated, the findings of Tsai et al should be interpreted with caution for the following reasons. First, the sample size for the subgroup analysis was limited (n=67 extreme myopes; 85 controls). Thus, the risk of a type I error was high. The moderate heterozygosity of rs667773 exacerbates this difficulty (hence the very low counts of TT genotypes). Second, the issue of population stratification was not considered. The MAF of rs667773 in the study of Tsai et al was 17%, suggesting that T allele is more common in Taiwanese than in hitherto studied populations. This wide variability in allele frequency could easily lead to a false–positive association if refractive error also varied across the region from which the subjects were sampled. Third, we note that the higher-risk C allele is more common in Europeans than in East Asians, whereas extreme myopia is more common in East Asia than in Europe. If rs667773 is an important myopia susceptibility variant, one would expect the opposite relationship. Fourth, according to the common disease, common variant hypothesis, for a high-risk variant to rise to a frequency >80%, it would have to exert a strong selective advantage. No such advantage has been attributed to the C allele of rs667773. Finally, unless the genetic risk factors for high and extreme myopia are distinct, the lack of association with high myopia is unexpected, especially since power was greater to detect an association with high myopia than extreme myopia.

Item Type: Article
Status: Published
Schools: Optometry and Vision Sciences
Additional Information: Correspondence
Publisher: Nature Publishing Group
ISSN: 0950-222X
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Last Modified: 17 Oct 2022 10:07

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